Diphenylmethane derivatives

ABSTRACT

The invention relates to novel diphenylmethane derivatives, processes for their preparation and their use in medicaments, in particular for the indications of arteriosclerosis and hypercholesterolaemia.

The invention relates to novel diphenylmethane derivatives, processesfor their preparation and their use in medicaments, in particular forthe indications of arteriosclerosis and hypercholesterolaemia.

European application 580 550 A describes oxamic acid derivatives havingcholesterol-lowering properties in mammals. This application describesan in vitro test based on the binding of thyroid hormone cell receptors(called T₃ nuclear receptors). Some of the compounds described thereinare stated to have IC-50 values of 0.2 nM and 0.1 nM in theL-triiodothyronine (LT₃) nuclear receptor test. The pharmacologicalproperty which is emphasized is the reduction in plasma cholesterol, inparticular LDL-cholesterol. Cholesterol-lowering effects are alsodescribed in the European application EP-A-188 351 for certain diphenylethers with thyroid hormone-like effects.

Tripp et al. in J. Med. Chem. 1973, 16(1), 60-64 describe the synthesisof methylene- and carbonyl-bridged analogs of iodothyronine. They foundthat their thyromimetic activity was less than that of the correspondingO- or S-bridged compounds.

Psychoyos et al. in Endocrinology 1973, 92(1), 243-250 also investigatedthe thyromimetic activity of methylene-bridged thyroid hormone analogs.They likewise concluded that the methylene-bridged compounds were lesspotent than the O-bridged compounds.

WO 98/57919 discloses selective thyroid hormone agonists with adiphenylmethane basic structure and their use in medicaments.

WO 99/26966 describes novel methods for designing ligands which bind tocertain receptors (called “nuclear receptors”). It is reported inparticular that molecules suitable for modulating the thyroid receptormust comply with certain three-dimensional requirements.

The invention relates to diphenylmethane derivatives of the generalformula (I)

in which

X is CH₂, CHF or CF₂,

R¹ is a group of the formula

—A—(CH₂)_(n)—[C(O)]_(m)—R⁷

 in which

A is CH₂, S, C(O) or NR⁸,

n is the number 0, 1, 2 or 3,

m is the number 1 or 2,

where m is the number 2 in the case where R² and R³ are halogen,

R⁷ is (C₁-C₆)-alkyl or a radical of the formula —NR⁹R¹⁰ or —OR¹¹,

in which

R⁸, R⁹, R¹⁰ and R¹¹ are identical or different and are, independently ofone another, hydrogen, (C₁-C₆)-alkyl or (C₁-C₈)-cycloalkyl,

R² and R³ are identical or different and are halogen, (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl, vinyl, CF₃, CHF₂ or CH₂F,

R⁴ is hydrogen, (C₁-C₆)-alkyl or (C₁-C₆)-acyl,

R⁵ is hydrogen, halogen, hydroxyl, cyano, CF₃, (C₁-C₆)-alkyl or(C₁-C₆)-alkoxy,

R⁶ is a radical of the formula

—(D)_(p)—R¹²

 in which

D is a group of the formula

 in which

R¹³ and R¹⁴ together are an oxo group or are identical or different andare hydrogen, halogen, hydroxyl, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy or aradical of the formula —NR¹⁵R¹⁶,

in which

R¹⁵ and R¹⁶ are identical or different and are hydrogen, benzyl,(C₁-C₆)-alkyl or (C₃-C₈)-cycloalkyl,

p is the number 0 or 1,

and

R¹² is hydrogen, OR¹⁷, NR¹⁸R¹⁹, (C₁-C₈)-alkyl, (C₃-C₈)-cycloalkyl,(C₆-C₁₀)-aryl or a saturated, unsaturated or aromatic 5- to 10-memberedheterocycle with up to three identical or different heteroatoms from theseries of S, O and/or N,

where

the aforementioned hydrocarbon radicals and heterocycles may optionallybe substituted once to three times, identically or differently, bysubstituents from the group of halogen, hydroxyl, oxo, cyano, nitro,amino, CF₃, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, (C₃-C₈)-cycloalkyl,—O—C(O)—R²⁰, —C(O)—O—R²¹, —C(O)—NR²²R²³ or —NH—C(O)—O—R²⁴,

and

in which

R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³ and R²⁴ are identical or different andare each, independently of one another, hydrogen, (C₁-C₆)-alkyl or(C₃-C₈)-cycloalkyl, each of which in turn may be substituted byhydroxyl, amino, mono- or di-(C₁-C₆)-alkylamino, phenyl, a saturated,unsaturated or aromatic 5- to 10-membered heterocycle with up to threeidentical or different heteroatoms from the series of S, O and/or N,

and the salts thereof.

Heterocycles which may be preferably mentioned in the definition of R¹²and R¹⁷ to R²⁴ are:

A 5- to 8-membered saturated, partly unsaturated or aromatic, optionallybenzo-fused heterocycle with up to 4 heteroatoms from the series of S, Nand/or O, i.e. a heterocycle which may contain one or more double bondsand which is linked via a ring carbon atom or a ring nitrogen atom.Examples which may be mentioned are: tetrahydrofur-2-yl,tetrahydrofur-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl,pyrrolin-1-yl, piperidin-1-yl, piperidin-3-yl, 1,2-dihydropyridin-1-yl,1,4-dihydropyridin-1-yl, piperazin-1-yl, morpholin-1-yl, azepin-1-yl,1,4-diazepin-1-yl, furan-2-yl, furan-3-yl, pyrrol-1-yl, pyrrol-2-yl,pyrrol-3-yl, thienyl, thiazolyl, oxazolyl, imidazolyl, triazolyl,tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyrimidinonyl, pyridazinonyl.

Preference is given to the following from this list: pyridyl, pyrimidyl,pyridazinyl, pyrimidinonyl, pyridazinonyl.

(C₁-C₈)-Alkyl, (C₁-C₆)-alkyl, (C₁-C₄)-alkyl and (C₁-C₃)-alkyl are forthe purposes of the invention a straight-chain or branched alkyl radicalrespectively with 1 to 8, 1 to 6, 1 to 4 and 1 to 3 carbon atoms. Astraight-chain or branched alkyl radical with 1 to 3 carbon atoms ispreferred. Examples which may be mentioned are: methyl, ethyl, n-propyl,isopropyl, t-butyl, n-pentyl and n-hexyl.

(C₆-C₁₀)-Aryl is for the purposes of the invention an aromatic radicalwith 6 to 10 carbon atoms. Preferred aryl radicals are phenyl andnaphthyl.

(C₃-C₈)-Cycloalkyl, (C₃-C₇)-cycloalkyl and (C₃-C₆)-cycloalkyl are forthe purposes of the invention a cycloalkyl group respectively with 3 to8, 3 to 7 and 3 to 6 carbon atoms. Those which may be mentioned aspreferred are: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl.

(C₁-C₆)-Alkoxy is for the purposes of the invention a straight-chain orbranched alkoxy radical with 1 to 6 carbon atoms. A straight-chain orbranched alkoxy radical with 1 to 3 carbon atoms is preferred. Exampleswhich may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy,t-butoxy, n-pentoxy and n-hexoxy.

(C₁-C₆)-Acyl is for the purposes of the invention particularly astraight-chain or branched alkyl radical with 1 to 6 carbon atoms whichhas a doubly bonded oxygen atom in the 1 position and is linked via the1 position. Examples which may be mentioned are: formyl, acetyl,propionyl, n-butyryl, i-butyryl, pivaloyl, n-hexanoyl.

Halogen includes for the purposes of the invention fluorine, chlorine,bromine and iodine. Fluorine, chlorine or bromine are preferred.

The compounds according to the invention may, depending on thesubstitution pattern, exist in stereoisomeric forms which either arerelated as image and mirror image (enantiomers) or are not related asimage and mirror image (diastereomers). The invention relates both tothe enantiomers or diastereomers and to respective mixtures thereof. Theracemic forms can, just like the diastereomers, be separated into thestereoisomerically pure constituents in a known manner.

Certain compounds may furthermore exist in tautomeric forms. This isknown to the skilled person, and such compounds are likewise encompassedby the scope of the invention.

The compounds according to the invention may also be in the form ofsalts. Physiologically acceptable salts are preferred for the purposesof the invention.

Physiologically acceptable salts may be salts of the compounds accordingto the invention with inorganic or organic acids. Preference is given tosalts with inorganic acids such as, for example, hydrochloric acid,hydrobromic acid, phosphoric acid or sulphuric acid, or salts with,organic carboxylic or sulphonic acids such as, for example, acetic acid,propionic acid, maleic acid, fumaric acid, malic acid, citric acid,tartaric acid, lactic acid, benzoic acid, or methanesulphonic acid,ethane-sulphonic acid, benzenesulphonic acid, toluenesulphonic acid ornaphthalenedisulphonic acid.

Physiologically acceptable salts may likewise be salts of the compoundsaccording to the invention with bases, such as, for example, metal orammonium salts. Preferred examples are alkali metal salts (for examplesodium or potassium salts), alkaline earth metal salts (for examplemagnesium or calcium salts), and ammonium salts which are derived fromammonia or organic amines such as, for example, ethylamine, di- ortriethylamine, ethyldiisopropylamine, ethanolamine, di- ortriethanolamine, dicyclohexylamine, dimethylaminoethanol, dibenzylamine,N-methylmorpholine, dihydroabietylamine, 1-ephenamine, methylpiperidine,arginine, lysine, ethylenediamine or 2-phenylethylamine.

The compounds according to the invention may also be in the form oftheir solvates, in particular in the form of their hydrates.

Preference is given to compounds of the general formula (I)

in which

X is CH₂, CHF or CF₂,

R¹ is a group of the formula

 —A—(CH₂)_(n)—[C(O)]_(m)—R⁷

 in which

 A is CH₂, C(O) or NR⁸,

n is the number 0, 1 or 2,

m is the number 1 or 2,

where m is the number 2 in the case where R² and R³ are halogen, or A isCH₂, and

n is not the number 1 when A is NH m is the number 1 and,

R⁷ is a radical of the formula —NR⁹R¹⁰ or —OR¹¹,

in which

R⁸, R⁹, R¹⁰ and R¹¹ are identical or different and, independently of oneanother, are hydrogen, (C₁-C₆)-alkyl or (C₃-C₈)-cycloalkyl,

R² and R³ are identical or different and are halogen, (C₁-C₆)-alkyl,cyclopropyl, vinyl, CF₃, CHF₂ or CH₂F,

R⁴ is hydrogen, (C₁-C₃)-alkyl or (C₁-C₃)-acyl,

R⁵ is hydrogen, halogen, CF₃, (C₁-C₃)-alkyl or (C₁-C₃)-alkoxy,

R⁶ is a radical of the formula

 —(D)_(p)—R¹²

 in which

D is a group of the formula

 in which

R¹³ and R¹⁴ together are an oxo group or are identical or different andare hydrogen, hydroxyl, (C₁-C₆)-alkyl,

p is the number 0 or 1,

and

R¹² is hydrogen, OR¹⁷, NR¹⁸R¹⁹, (C₁-C₈)-alkyl, (C₃-C₈)-cycloalkyl,(C₆-C₁₀)-aryl or a saturated, unsaturated or aromatic 5- to 6-memberedheterocycle with up to three identical or different heteroatoms from theseries of S, O and/or N,

where

the aforementioned hydrocarbon radicals and heterocycles may optionallybe substituted once to three times, identically or differently, bysubstituents from the group of halogen, hydroxyl, oxo, cyano, nitro,amino, CF₃, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, (C₃-C₈)-cycloalkyl,—O—C(O)—R²⁰, —C(O)—O—R²¹, —C(O)—NR²²R²³ or —NH—C(O)—O—R²⁴,

and

in which

R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³ and R²⁴ are identical or different andare each, independently of one another, hydrogen, (C₁-C₆)-alkyl or(C₃-C₈)-cycloalkyl, each of which in turn may be substituted byhydroxyl, amino, mono- or di-(C₁-C₆)-alkylamino, phenyl, a saturated,unsaturated or aromatic 5- to 6-membered heterocycle with up to threeidentical or different heteroatoms from the series of S, O and/or N,

and the salts thereof.

Of particular importance are compounds of the general formula (I)

in which

X is CH₂, CHF or CF₂,

R¹ is a group of the formula —NH—C(O)—C(O)—OR¹¹,

in which

R¹¹ is hydrogen or (C₁-C₄)-alkyl,

R² and R³ are identical or different and are halogen, (C₁-C₄)-alkyl,cyclopropyl, CF₃, CHF₂ or CH₂F,

R⁴ is hydrogen or (C₁-C₃)-alkyl,

R⁵ is hydrogen,

and

R⁶ is (C₁-C₆)-alkyl or (C₃-C₆)-cycloalkyl or is a radical of the formula

 in which

R¹² is phenyl, pyrimidinyl, pyridyl or 3(2H)-pyridazinonyl, each ofwhich may be substituted up to three times, identically or differently,by halogen, hydroxyl, trifluoromethyl, (C₁-C₃)-alkyl or (C₁-C₃)-alkoxy,or is a radical of the formula —NR¹⁸R¹⁹,

in which

R¹⁸ and R¹⁹ are identical or different and are, independently of oneanother, (C₁-C₄)-alkyl which may be substituted by hydroxyl, amino,mono- or di-(C₁-C₄)-alkylamino, or by phenyl, pyridyl or pyrimidinyl,each of which is optionally substituted up to three times by hydroxyl,halogen, trifluoromethyl, methoxy or (C₁-C₃)-alkyl,

R¹³ and R¹⁴ together are an oxo group or are identical or different andare hydrogen, hydroxyl, (C₁-C₆)-alkyl,

and the salts thereof.

Preferred compounds of the formula (I) are those in which R² and R³ aremethyl.

Preferred compounds of the formula (I) are those in which R⁵ ishydrogen. Preferred compounds of the formula (I) are those in which R⁴is methyl or hydrogen. The compounds according to the invention of thegeneral formula (I) can be prepared by reacting reactive phenolderivatives of the general formula (II) with reactive phenyl derivativesof the general formula (III)

where the substituents R¹′, R²′, R³′, R⁴′, R⁵′ and R⁶′ have the meaningsstated above for R¹ to R⁶, and

Z and Y are each groups of opposite reactivity, it being possible forexample for Z to be an electrophilic radical which reacts with anucleophilic Y substituent, and vice versa,

X′ has the meaning stated for X or is

where appropriate in the presence of inert solvents and catalysts and,where appropriate, with isolation of the intermediates of the generalformula (Ia) in which X′ is —CH(OH)— or directly to give compounds ofthe formula (I).

Examples of catalysts which may be mentioned are coupling catalysts suchas Pd compounds and/or Cu compounds.

Examples which may be mentioned of reactive groups Z and Y are: formyl,CH₂Hal (Hal=halogen, in particular Cl, Br or I), CH₂OTosyl, Li, MgHal,and derivatives of Cu, Pd, Sn or boron.

The phenol derivatives of the general formula (II) which can be employedaccording to the invention are known or can be prepared by known methods(compare, for example, Chemistry & Biology 1998, 5, 299-306, J. Org.Chem. 1956, 21, 1458).

The phenyl derivatives of the general formula (III) are likewise knownor can be prepared by known methods (compare, for example, J. Med. Chem.1997, 40, 3542-3550 and the references stated above for the phenolderivatives of the formula (II)).

The reaction of the starting compounds (II) with (III) generallyproceeds under atmospheric pressure. However, it can also be carried outunder elevated or reduced pressure.

The reaction can be carried out in a temperature range from −100° C. to200° C., preferably between −78° C. and 150° C. in the presence of inertsolvents. Inert solvents which may be mentioned as preferred are:dimethyl sulphoxide (DMSO), dimethylformamide (DMF), tetrahydrofuran(THF), diethyl ether etc.

Depending on the specific substitution pattern, the reaction of (II) and(III) may also result in intermediates of the formula (Ia) in which X′is a CHOH group, which can then be reduced, with or without isolation ofthese intermediates, by conventional methods to the correspondingmethylene group.

The process according to the invention can be illustrated by way ofexample by the following formula diagrams:

Process Variant (A)

Process Variant (B)

Depending on the meaning of the substituents R¹′, R²′, R⁴′, R⁵′, and R⁶′it may be sensible or necessary for them to be varied at individualstages of the process within the stated scope of the meanings.Intermediate protection with conventional protective groups may also benecessary for particular substituents, which are liberated again at alater stage by elimination of the protective group.

Protective groups mean in the present application those groups which, instarting, intermediate and/or final products, protect functional groupswhich, are present, such as, for example, carboxyl, amino or hydroxylgroups, and which are customary in preparative organic chemistry. Thegroups protected in this way can then be converted into free functionalgroups in a simple manner under known conditions.

This invention likewise relates to the precursors or intermediates ofthe formula (Ia), in which X′ is —CH(OH)— and which occur in thereaction of (II) and (III). They have essential structural features ofthe compounds according to the invention of the formula (I) and theirprodrugs and thus meet all the requirements for patenting as novelintermediates.

The compounds according to the invention of the formula (I) show asurprising and valuable range of pharmacological actions and cantherefore be employed as versatile medicaments. In particular, they canbe employed for all indications which can be treated with naturalthyroid hormones, such as, for example and preferably, depression,goitre or thyroid cancer. It is possible and preferred to use thecompounds according to the invention of the formula (I) to treatarteriosclerosis, hypercholesterolaemia and dyslipidaemia. It isadditionally possible to treat adiposity and corpulence (obesity) andheart failure, and achieve a postprandial reduction in triglycerides.

The compounds are also suitable for the treatment of certain airwaydisorders, in particular pulmonary emphysemas, and for medicallypromoting maturation of the lungs.

The compounds are also suitable for the treatment of Alzheimer'sdisease.

The compounds are furthermore suitable for the treatment ofosteoporosis, cardiac arrhythmias, hypothyroidism and skin disorders.

The compounds can additionally be employed for the promotion andregeneration of hair growth.

The active substances according to the invention open up a furthertreatment alternative and represent an enrichment of pharmacy. Comparedwith known and previously employed thyroid hormone products, thecompounds according to the invention show an improved range of action.They are preferably distinguished by great specificity, goodtolerability and fewer side effects, in particular in the cardiovasculararea.

Their activity can be tested, for example, in vitro by the following T3promoter assay cell test:

The test is carried out with a stably transfected human HepG2hepatocarcinoma cell which expresses a luciferase gene under the controlof a thyroid hormone-regulated promoter. The vector used for thetransfection has upstream of the luciferase gene a minimal thymidinekinase promoter with a thyroid hormone-responsive element (TRE) whichconsists of two inverted palindromes each of 12 bp and of an 8 bpspacer.

For the test, the cell cultures are seeded in Eagle's minimal essentialmedium in 96-well plates with the following additions: glutamine,tricine, sodium pyruvate, nonessential amino acids, insulin, seleniumand transferrin. The cultures are grown at 37° C. with a 10% CO₂atmosphere for 48 hours. Then serial dilutions of test substance orreference compound (T3, T4) and costimulator retinoic acid are added tothe test cultures and the latter are incubated as previously for afurther 48 or 72 hours. Each substance concentration is tested in fourreplicates. To determine the luciferase induced by T3 or othersubstances, the cells are subsequently lysed by adding a Triton- andluciferin-containing buffer and measured immediately in a luminometer.The EC₅₀ values for each compound are calculated (see Table 1).

TABLE 1 Example EC₅₀ [nM] 2 0.14 4 0.23 5 4.3 

The compounds according to the invention also show surprisinglyadvantageous properties in the in vivo test described below:

Description of test for finding pharmacologically active substanceswhich lower the serum cholesterol in mice:

The substances to be investigated for their serum cholesterol-loweringeffect in vivo are administered orally to male mice with a body weightbetween 25 and 35 g. One day before starting the test, the animals aredivided into groups with an identical number of animals, usually n=7-10.Throughout the test drinking water and feed are available ad libitum tothe animals. The substances are administered orally once a day for 7days. For this purpose, the test substances are dissolved in a solutionof Solutol HS 15+ethanol+saline (0.9%) in the ratio 1+1+8 or in asolution of Solutol HS 15+saline (0.9%) in the ratio 2+8. The dissolvedsubstances are administered by gavage in a volume of 10 ml/kg of bodyweight. Animals treated in exactly the same way but receiving only thesolvent (10 ml/kg of body weight) without test substance serve ascontrol group.

Before the first administration of substance, blood is taken from eachmouse by puncture of the retroorbital venous plexus for determination ofthe serum cholesterol (initial value). The test substance is thenadministered to the animals by gavage for the first time. 24 hours afterthe last administration of substance (on the 8th day after the start oftreatment), blood is again taken from each animal by puncture of theretroorbital venous plexus for determination of the serum cholesterol.The blood samples are centrifuged and, after the serum is obtained, thecholesterol is determined by photometry using an EPOS analyser 5050(Eppendorf-Gerätebau, Netheler & Hinz GmbH, Hamburg). The determinationtakes place with a commercially available enzyme assay (BoehringerMannheim, Mannheim).

The effect of the test substances on the serum cholesterol concentrationis determined by subtracting the cholesterol level in the 1st bloodsample (initial value) from the cholesterol level in the 2nd bloodsample (after treatment). The differences of all the cholesterol levelsin a group are averaged and compared with the average of the differencesin the control group.

Statistical analysis takes place using Student's t test after previouschecking of the variants for homogeneity.

Substances which reduce the serum cholesterol in the treated animalscompared with the control group statistically significantly (p<0.05) byat least 10% are judged as pharmacologically active.

Administration forms suitable for administering the compounds of thegeneral formula (I) are all conventional ones, that is to say oral,parenteral, inhalation, nasal, sublingual, rectal or externals, such as,for example, transdermal, particularly preferably oral or parenteral. Inconnection with parenteral administration, particular mention should bemade of intravenous, intramuscular, subcutaneous administration, forexample as subcutaneous depot. Oral administration is very particularlypreferred.

The active substances can in this connection be administered alone or inthe form of preparations. Preparations suitable for oral administrationare, inter alia, tablets, capsules, pellets, coated tablets, pills,granules, solid and liquid aerosols, syrups, emulsions, suspensions andsolutions. The active substance must be present in an amount such that atherapeutic effect is achieved. In general, the active substance can bepresent in a concentration of from 0.1 to 100% by weight, in particularfrom 0.5 to 90% by weight, preferably from 5 to 80% by weight. Theconcentration of active substance should, in particular, be 0.5-90% byweight, that is, to say the active substance should be present inamounts sufficient to reach the stated dose range.

For this purpose, the active substances can be converted in a mannerknown per se into the customary preparations. This takes place by use ofinert, nontoxic, pharmaceutically acceptable carriers, excipients,solvents, vehicles, emulsifiers and/or dispersants.

Examples of excipients which may be mentioned are: water, nontoxicorganic solvents such as, for example, paraffins, vegetable oils (forexample sesame oil), alcohols (for example ethanol, glycerol), glycols(for example polyethylene glycol), solid carriers such as natural, orsynthetic ground minerals (for example talc or silicates), sugars (forexample lactose), emulsifiers, dispersants (for examplepolyvinylpyrrolidone) and lubricants (for example magnesium sulphate).

In the case of oral administration, tablets can, of course, also containadditions such as sodium citrate together with additives such as starch,gelatin and the like. Aqueous preparations for oral administration mayfurthermore include flavour improvers or colorants.

The dosages administered on oral administration are preferably from0.001 to 5 mg/kg, preferably 0.005 to 3 mg/kg, of body weight every 24hours.

The novel active substances can be administered alone and, if required,also in combination with other active substances, preferably from thegroup of CETP inhibitors, antidiabetics, antioxidants, cytostatics,calcium antagonists, blood pressure-lowering agents, thyroid hormones,inhibitors of HMG-CoA reductase gene expression, inhibitors of HMG-CoAreductase, squalene synthesis inhibitors, ACAT inhibitors,perfusion-promoting agents, platelet aggregation inhibitors,anticoagulants, angiotensin-II receptor antagonists, cholesterolabsorption inhibitors, MTP inhibitors, fibrates, niacin and PPARagonists.

The following examples are intended to illustrate the invention by wayof example without a restrictive effect on the scope of protection.

EXAMPLES

Starting Compounds

Example I

2,6-Dimethyl-4-nitrophenyl trifluoromethanesulphonate

A solution of 150 g (0.9 mol) of dimethylnitrophenol in 700 ml ofdichloromethane is cooled to −15° C. 181 ml of pyridine are added. 308.8g (1.09 mol) of trifluoromethanesulphonic anhydride are then metered indropwise over a period of 2 h in such a way that the reactiontemperature does not exceed −5° C. Then, at a temperature of −5° C., 150ml of water are added. The organic phase is extracted successively withHCl (1 molar, about 300 ml) and water (twice), each at 3-5° C. Thesolvent is removed in vacuo, and the residue is stirred with petroleumether. The precipitate is filtered off with suction. A further fractionis obtained by cooling the mother liquor. Yield: 232 g (85%)

¹H-NMR (200 MHz, CDCl₃): 2.50, s, 6H; 8.04, s, 2H.

Example II

2-Bromo-1,3-dimethyl-5-nitrobenzene

10.7 g (35.8 mmol) of 2,6-dimethyl-4-nitrophenyltrifluoromethanesulphonate (Example I) and 4.84 g (55.8 mmol) of LiBrare stirred in 120 ml of N-methylpyrrolidinone at 120° C. for 41 h.(Solvent: ethyl acetate/cyclohexane 1:4). After cooling, 80 ml of waterare slowly added, and the mixture is stirred while cooling in an icebathfor 1 h. The precipitate is filtered off with suction and stirred with200 ml of petroleum ether. The solvent is removed in vacuo. 7.23 g (85%)of solid are obtained.

¹H-NMR (200 MHz, DMSO-D₆): 2.52, s, 6H; 8.02, s, 2H.

Example III

4-Bromo-3,5-dimethylaniline

153 g of tin dichloro dihydrate (678 mmol) are added to 1.7 l of conc.HCl and heated to about 50° C. 26 g (113 mmol) of2-bromo-1,3-dimethyl-5-nitrobenzene (Example II) are added. Thesuspension is heated at about 70° C. for 20 min. It is then allowed tocool slowly to room temperature. The precipitated white solid isfiltered off and washed with cold acetone. The resulting hydrochlorideis taken up in 1 N NaOH, briefly stirred and extracted 5 times withethyl acetate. The organic phases are combined and dried over sodiumsulphate, and the solvent is removed in vacuo.

¹H-NMR (200 MHz, DMSO-D₆): 2.19, s, 6H; 5.21, s, broad, 2H; 6.39, s, 2H

Example IV

tert-Butyl 4-bromo-3,5-dimethylphenylcarbamate

4 g (14.9 mmol) of 4-bromo-3,5-dimethylaniline (Example III) and 4.2 g(19.4 mmol) of di-tert-butyl pyrocarbamate are heated under reflux in150 ml of THF for 5 hours. The solvent is removed in vacuo, the residueis taken up in ether and the solution is washed successively with 10%strength citric acid solution, sodium bicarbonate solution and water.The organic phase is dried over sodium sulphate, and the solvent isremoved in vacuo. 4.3 g (95%) of tert-butyl4-bromo-3,5-dimethylphenylcarbamate are obtained.

¹H-NMR (200 MHz, DMSO-D₆): 1.47, s, 9H; 2.28, s, 6H; 7.29, s, 2H; 9.39,s, 1H.

Example V

tert-Butyl4-[hydroxy(4-methoxy-3-isopropylphenyl)methyl]-3,5-dimethylphenylcarbamate

970 mg (3.23 mmol) of tert-butyl 4-bromo-3,5-dimethylphenylcarbamate(Example IV) are dissolved in 3 ml of cyclohexane and 3 ml of ether,cooled to −78° C., and added dropwise to 2.53 ml of 1.6 M methyllithiumin ether at −78° C. After stirring at this temperature for 10 minutes,3.8 ml of 1.7 M tert-butyllithium in pentane are added dropwise. Themixture is stirred at −78° C. for 1 hour and, after addition of 518 mg(2.9 mmol) of 3-isopropyl-4-methoxybenzaldehyde dissolved in 1 ml ofether/cyclohexane (1/1), stirred at −78° C. for 30 min and at roomtemperature for one hour. It is diluted with water and ether, theorganic phase is washed with 10% strength citric acid solution, sodiumbicarbonate solution and water and dried over sodium sulphate, and thesolvent is removed in vacuo. Purification by chromatography(cyclohexane/ethyl acetate=9:1) affords 0.76 g (53%) of tert-butyl4-[hydroxy(4-methoxy-3-isopropylphenyl)methyl]-3,5-dimethylphenylcarbamate.

¹H-NMR (400 MHz, CDCl₃): 1.16, d, 3H; 1.20, d, 3H; 1.52, s, 9H; 2.05, d,1H; 2.225, s, 6H; 3.28, hept, 1H; 3.81, s, 3H; 6.26, d, 1H; 6.40, s, 1H;6.72, m, 1H; 6.90, dd, 1H; 7.06, s, 2H; 7.22, m, 1H.

Example VI

tert-Butyl 4-(4-methoxy-3-isopropylbenzyl)-3,5-dimethylphenylcarbamate

730 mg (1.66 mmol) of tert-butyl4-[hydroxy(4-methoxy-3-isopropylphenyl)methyl]-3,5-dimethylphenylcarbamate(Example V) are hydrogenated with 700 mg of Pd/C (10%) and with 1 bar ofhydrogen at RT for 4 hours. The mixture is filtered through kieselguhr,the solvent is removed in vacuo, and purification by chromatographyresults in 578 mg (91%) of tert-butyl4-(4-methoxy-3-isopropylbenzyl)-3,5-dimethylphenylcarbamate.

¹H-NMR (400 MHz, CDCl₃): 1.18, d, 6H; 1.52, s, 9H; 2.21, s, 6H; 3.26,hept, 1H; 3.78, s, 3H; 3.92, s, 2H; 6.38, s, 1H; 6.63, m, 2H; 6.95, m,1H; 7.08, s, 2H.

Example VII

4-(3-Isopropyl-4-methoxybenzyl)-3,5-dimethylaniline

578 mg (1.36 mmol) of tert-butyl4-(4-methoxy-3-isopropylbenzyl)-3,5-dimethylphenylcarbamate (Example VI)are dissolved in 10 ml of 5% trifluoroacetic acid in dichloromethane at0° C. and stirred for 4 hours. The mixture is neutralized with sodiumbicarbonate solution and dried over sodium sulphate. The product afterremoval of the solvent is reacted further without further purification.

¹H-NMR (400 MHz, CDCl₃): 1.16, d, 6H; 2.16, s, 6H; 3.26, hept, 1H; 3.78,s, 3H; 3.89, s, 2H; 6.45, m, 1H; 6.68, m, 1H; 6.95, s, 1H.

Example VIII

tert-Butyl4-[[3-(4-fluorobenzyl)-4-methoxyphenyl](hydroxy)methyl]-3,5-dimethylphenylcarbamate

1.3 ml of methyllithium (2.1 mmol, 1.6 M in diethyl ether) areintroduced into 1 ml of diethyl ether and, at −78° C., 600 mg (1.99mmol) of tert-butyl 4-bromo-3,5-dimethylphenylcarbamate (Example IV) in2 ml of diethyl ether/1 ml of THF are added. After 20 min, 1.53 ml oft-BuLi (2.6 mmol, 1.7 M in pentane) are added dropwise and the mixtureis stirred at −78° C. for 30 min.3-(4-Fluorobenzyl)-4-methoxybenzaldehyde dissolved in 3 ml of THF isadded dropwise. After stirring at −78° C. for 1 h, aqueous NH₄Clsolution is added. The mixture is diluted with diethyl ether andextracted with water, and the organic phase is dried and concentrated ina rotary evaporator. Chromatography (cyclohexane/ethyl acetate=6:1)affords 493 mg (46%) of tert-butyl4-[[3-(4-fluorobenzyl)-4-methoxyphenyl](hydroxy)methyl]-3,5-dimethylphenylcarbamate.

¹H-NMR (300 MHz, CDCl₃): 1.52, s, 9H; 2.21, s, 6H; 3.78, s, 3H; 3.90, d,2H; 6.20, d, broad, 1H; 6.38, s, broad, 1H; 6.77, d, 1H; 6.90, m, 4H;7.05, s, 2H; 7.10, m, 3H.

Example IX

tert-Butyl4-[3-(4-fluorobenzyl)-4-methoxybenzyl]-3,5-dimethylphenylcarbamate

590 mg of tert-butyl4-[[3-(4-fluorobenzyl)-4-methoxyphenyl](hydroxy)methyl]-3,5-dimethylphenylcarbamate(Example VIII), 24 mg of Pd/carbon (10%) and a drop of acetic acid arehydrogenated in 10 ml of methanol with hydrogen at atmospheric pressurefor 4 h. The suspension is filtered through kieselguhr. The filtrate isconcentrated in a rotary evaporator. Chromatography (cyclohexane/ethylacetate=6:1) affords 449 mg (77%) of tert-butyl4-[3-(4-fluorobenzyl)-4-methoxybenzyl]-3,5-dimethylphenylcarbamate.

¹H-NMR (300 MHz, CDCl₃): 1.52, s, 9H; 2.19, s, 6H; 3.72, s, 3H; 3.85, d,4H; 6.72, m, 3H; 6.92, m, 2H; 7.05, m, 4H.

Example X

4-[3-(4-Fluorobenzyl)-4-methoxybenzyl]-3,5-dimethylaniline

460 mg (1.02 mmol) of tert-butyl4-[3-(4-fluorobenzyl)-4-methokybenzyl]-3,5-dimethylphenylcarbarnate(Example IX) are stirred in 10 ml of trifluoroaceticacid/dichloromethane (10% strength solution) at room temperatureovernight. After neutralization with NaHCO₃ solution, the organic phaseis separated, dried over sodium sulphate and concentrated in a rotaryevaporator. Chromatography (cyclohexane/ethyl acetate=6:1) affords 218mg (55%) of 4-[3-(4-fluorobenzyl)-4-methoxybenzyl]-3,5-dimethylaniline.

¹H-NMR (300 MHz, CDCl₃): 2.22, s, 6H; 3.56, s, broad 2H; 3.74, s, 3H;3.82, s, 2H; 3.85, s, 2H;

Exemplary Embodiments

Example 1

Ethyl2-[4-(3-isopropyl-4-methoxybenzyl)-3,5-dimethylanilino]-2-oxoacetate

246 mg (0.86 mmol) of4-(3-isopropyl-4-methoxybenzyl)-3,5-dimethylaniline (Example VII) aredissolved with 97 mg (0.96 mmol) of triethylamine in 10 ml ofdichloromethane, and 160 mg (1.17 mmol) of ethoxalyl chloride are addeddropwise. The mixture is stirred at room temperature for 4 hours, washedwith sodium bicarbonate solution and water and dried over sodiumsulphate, and the solvent is removed in vacuo. Purification bychromatography affords 128 mg (38%) of ethyl2-[4-(3-isopropyl-4-methoxybenzyl)-3,5-dimethylanilino]-2-oxoacetate.

R_(f)=0.63 (toluene/acetonitrile=9:1).

Example 2

2-[4-(4-Hydroxy-3-isopropylbenzyl)-3,5-dimethylanilino]-2-oxoacetic acid

128 mg (0.33 mmol) of ethyl2-[4-(3-isopropyl-4-methoxybenzyl)-3,5-dimethyl-anilino]-2-oxoacetate(Example 1) in 5 ml of dichloromethane at −78° C. under argon aretreated dropwise with 167 mg (0.66 mmol) of boron tribromide. Thereaction mixture is stirred at room temperature for 2.5 hours. It ispoured into buffer of pH 7, the phases are separated, the aqueous phaseis acidified with buffer of pH 4 and, after extraction withdichloromethane, the organic phases are combined. The solution is driedover sodium sulphate and the solvent is removed in vacuo. 112 mg (98%)of 2-[4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylanilino]-2-oxoaceticacid are obtained.

¹H-NMR (400 MHz, CDCl₃): 1.21, d, 6H; 2.26, s, 6H; 3.15, hept, 1H; 3.95,s, 2H; 4.52, s, broad, 1H; 6.57, m, 2H; 6.91, m, 1H; 7.32, s, 2H; 8.83,s, broad, 1H.

Example 3

Ethyl({4-[3-(4-fluorobenzyl)-4-methoxybenzyl]-3,5-dimethylphenyl}amino)(oxo)-acetate

335 mg (0.96 mmol) of4-[3-(4-fluorobenzyl)-4-methoxybenzyl]-3,5-dimethylaniline (Example X)and 107 mg (1.06 mmol) of triethylamine are introduced into ml ofdichloromethane and, at 0° C., 177 mg (1.29 mmol) of ethoxalyl chlorideare added dropwise. The mixture is stirred for 4 h. It is shaken withNaHCO₃ solution and NaCl solution, and the organic phase is dried andconcentrated in a rotary evaporator. Purification by chromatography(cyclohexane/ethyl acetate=7:1) affords 231 mg of ethyl({4-[3-(4-fluorobenzyl)-4-methoxybenzyl]-3,5-dimethylphenyl}amino)(oxo)-acetate.

¹H-NMR (400 MHz, DMSO-D₆): 1.21, t, 3H; 2.21, s, 6H; 3.42, quart, 2H;3.74, s, 4H; 6.71, m, 2H; 6.92, m, 3H; 7.10, m 2H; 7.31, s, 2H; 8.73, s,1H.

Example 4

({4-[3-(4-Fluorobenzyl)-4-hydroxybenzyl]-3,5-dimethylphenyl}amino)(oxo)aceticacid

102 mg (0.22 mmol) of ethyl({4-[3-(4-fluorobenzyl)-4-methoxybenzyl]-3,5-dimethylphenyl}amino)(oxo)acetate(Example 3) in 5 ml of dichloromethane at −78° C. under argon aretreated slowly with 65 mg (0.25 mmol) of BBr₃. The reaction mixture isstirred overnight while reaching room temperature. It is again cooled to−78° C. and a further 65 mg (0.25 mmol) of BBr₃ is added. The mixture isstirred at room temperature for 2 hours. Pouring into ice-water,stirring for 2 hours, extraction with dichloromethane and ethyl acetateand drying over sodium sulphate are followed by concentration in arotary evaporator. The residue is stirred with ether and the solid isfiltered off with suction. 51 mg (48%) of({4-[3-(4-fluorobenzyl)-4-hydroxy-benzyl]-3,5-dimethylphenyl}amino)(oxo)aceticacid are obtained.

¹H-NMR (400 MHz, DMSO-D₆): 2.12, s, 6H; 3.78, s, 4H; 6.61, m, 4H; 7.05,m, 2H; 7.18, m, 2H; 7.49, s, 2H; 9.20, s, 1H; 9.91, s, 1H.

Example 5

({4-[3-(4-Fluorobenzyl)-4-methoxybenzyl]-3,5-dimethylphenyl}amino)(oxo)aceticacid

290 mg (0.64 mmol) of ethyl({4-[3-(4-fluorobenzyl)-4-methoxybenzyl]-3,5-dimethylphenyl-}amino)(oxo)acetate(Example 3) in 8 ml of dichloromethane at −78° C. under argon aretreated slowly with 356 mg (1.41 mmol) of BBr₃. The mixture is allowedto fall to room temperature and is stirred for 2.5 h. The reactionmixture is poured into buffer of pH 7, the organic phase is separatedoff, and the pH of the aqueous phase is adjusted to pH 7 and it is thenextracted. The combined organic phases are washed with saturated NaClsolution, dried and concentrated in a rotary evaporator. The residue isstirred with diethyl ether, filtered off with suction and dried.

¹H-NMR (300 MHz, CDCl₃): 2.22, s, 6H; 3.75, s, 3H; 3.85, s, 2H; 3.92, s,2H; 6.61, m, 3H; 6.91, m, 2H; 7.09, m, 2H; 7.30, s, 2H; 8.82, s, 1H.

What is claimed is:
 1. Compounds of the general formula (I)

in which X is CH₂, CHF or CF₂, R¹ is a group of the formula—A—(CH₂)_(n)—[C(O)]_(m)—R⁷  in which A is CH₂, S, C(O) or NR⁸, n is thenumber 0, 1, 2 or 3, m is the number 1 or 2, where m is the number 2 inthe case where R² and R³ are halogen, R⁷ is (C₁-C₆)-alkyl or a radicalof the formula —NR⁹R¹⁰ or —OR¹¹, in which R⁸, R⁹, R¹⁰ and R¹¹ areidentical or different and are, independently of one another, hydrogen,(C₁-C₆)-alkyl or (C₃-C₈)-cycloalkyl, R² and R³ are identical ordifferent and are halogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, vinyl,CF₃, CHF₂ or CH₂F, R⁴ is hydrogen, (C₁-C₆)-alkyl or (C₁-C₆)-acyl, R⁵ ishydrogen, halogen, hydroxyl, cyano, CF₃, (C₁-C₆)-alkyl or(C₁-C₆)-alkoxy, R⁶ is a radical of the formula —(D)_(p)—R¹²  in which Dis a group of the formula

 in which R¹³ and R¹⁴ together are an oxo group or are identical ordifferent and are hydrogen, halogen, hydroxyl, (C₁-C₆)-alkyl,(C₁-C₆)-alkoxy or a radical of the formula —NR¹⁵R¹⁶, in which R¹⁵ andR¹⁶ are identical or different and are hydrogen, benzyl, (C₁-C₆)-alkylor (C₃-C₈)-cycloalkyl, p is the number 0 or 1, and R¹² is hydrogen,OR¹⁷, NR¹⁸R¹⁹, (C₁-C₈)-alkyl, (C₃-C₈)-cycloalkyl, (C₆-C₁₀)-aryl or asaturated, unsaturated or aromatic 5- to 10-membered heterocycle with upto three identical or different heteroatoms from the series of S, Oand/or N, where the aforementioned hydrocarbon radicals and heterocyclesmay optionally be substituted once to three times, identically ordifferently, by substituents from the group of halogen, hydroxyl, oxo,cyano, nitro, amino, CF₃, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy,(C₃-C₈)-cycloalkyl, —O—C(O)—R²⁰, —C(O)—O—R²¹, —C(O)—NR²²R²³ or—NH—C(O)—O—R²⁴, and in which R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³ and R²⁴are identical or different and are each, independently of one another,hydrogen, (C₁-C₆)-alkyl or (C₃-C₈)-cycloalkyl, each of which in turn maybe substituted by hydroxyl, amino, mono- or di-(C₁-C₆)-alkylamino,phenyl, a saturated, unsaturated or aromatic 5- to 10-memberedheterocycle with up to three identical or different heteroatoms from theseries of S, O and/or N, and the salts thereof.
 2. Compounds of theformula (I) according to claim 1, in which X is CH₂, CHF or CF₂, R¹ is agroup of the formula —A—(CH₂)_(n)—[C(O)]_(m)—R⁷  in which A is CH₂, C(O)or NR⁸, n is the number 0, 1, or 2, m is the number 1 or 2, where m isthe number 2 in the case where R² and R³ are halogen, or A is CH₂, and nis not the number 1 when A is NH and m is the number 1 and, R⁷ is aradical of the formula —NR⁹R¹⁰ or —OR¹¹, in which R⁸, R⁹, R¹⁰ and R¹¹are identical or different and, independently of one another, arehydrogen, (C₁-C₆)-alkyl or (C₃-C₈)-cycloalkyl, R² and R³ are identicalor different and are halogen, (C₁-C₆)-alkyl, cyclopropyl, vinyl, CF₃,CHF₂ or CH₂F, R⁴ is hydrogen, (C₁-C₃)-alkyl or (C₁-C₃)-acyl, R⁵ ishydrogen, halogen, CF₃, (C₁-C₃)-alkyl or (C₁-C₃)-alkoxy, R⁶ is a radicalof the formula —(D)_(p)—R¹²  in which D is a group of the formula

 in which R¹³ and R¹⁴ together are an oxo group or are identical ordifferent and are hydrogen, hydroxyl, (C₁-C₆)-alkyl, p is the number 0or 1, and R¹² is hydrogen, OR¹⁷, NR¹⁸R¹⁹, (C₁-C₆)-alkyl,(C₃-C₈)-cycloalkyl, (C₆-C₁₀)-aryl or a saturated, unsaturated oraromatic 5- to 6-membered heterocycle with up to three identical ordifferent heteroatoms from the series of S, O and/or N, where theaforementioned hydrocarbon radicals and heterocycles may optionally besubstituted once to three times, identically or differently, bysubstituents from the group of halogen, hydroxyl, oxo, cyano, nitro,amino, CF₃, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, (C₃-C₈)-cycloalkyl,—O—C(O)—R²⁰, —C(O)—O—R²¹, —C(O)—NR²²R²³ or —NH—C(O)—O—R²⁴, and in whichR¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³ and R²⁴ are identical or different andare each, independently of one another, hydrogen, (C₁-C₆)-alkyl or(C₃-C₈)-cycloalkyl, each of which in turn may be substituted byhydroxyl, amino, mono- or di-(C₁-C₆)-alkylamino, phenyl, a saturated,unsaturated or aromatic 5- to 6-membered heterocycle with up to threeidentical or different heteroatoms from the series of S, O and/or N, andthe salts thereof.
 3. Compounds of the formula (I) according to claim 1,in which X is CH₂, CHF or CF₂, R¹ is a group of the formula—NH—C(O)—C(O)—OR¹¹, in which R¹¹ is hydrogen or (C₁-C₄)-alkyl, R² and R³are identical or different and are halogen, (C₁-C₄)-alkyl, cyclopropyl,CF₃, CHF₂ or CH₂F, R⁴ is hydrogen or (C₁-C₃)-alkyl, R⁵ is hydrogen, andR⁶ is (C₁-C₆)-alkyl or (C₃-C₆)-cycloalkyl or is a radical of the formula

 in which R¹² is phenyl, pyrimidinyl, pyridyl or 3(2H)-pyridazinonyl,each of which may be substituted up to three times, identically ordifferently, by halogen, hydroxyl, trifluoromethyl, (C₁-C₃)-alkyl or(C₁-C₃)-alkoxy, or is a radical of the formula —NR¹⁸R¹⁹, in which R¹⁸and R¹⁹ are identical or different and are, independently of oneanother, (C₁-C₄)-alkyl which may be substituted by hydroxyl, amino,mono- or di-(C₁-C₄)-alkylamino, or by phenyl, pyridyl or pyrimidinyl,each of which is optionally substituted up to three times by hydroxyl,halogen, trifluoromethyl, methoxy or (C₁-C₃)-alkyl, R¹³ and R¹⁴ togetherare an oxo group or are identical or different and are hydrogen,hydroxyl, (C₁-C₆)-alkyl, and the salts thereof.
 4. Process for preparingcompounds of the general formula (I) as defined in claim 1,characterized in that reactive phenol derivatives of the general formula(II) are reacted with reactive phenyl derivatives of the general formula(III)

where the substituents R¹′, R²′, R³′, R⁴′, R⁵′ and R⁶′ have the meaningsstated for R¹ to R⁶ in claim 1, and Z and Y are each groups of oppositereactivity, X′ has the meaning stated for X in claim 1 or is


5. Compounds of the general formula (Ia)

in which R¹′, R²′, R³′, R⁴′, R⁵′ and R⁶′ have the meanings stated for R¹to R⁶ in claim 1, X′ is —CH(OH)—, and the salts thereof.
 6. Medicamentcontaining at least one compound of the general formula (I) according toclaim
 1. 7. Process for producing medicaments, characterized in that atleast one compound of the general formula (I) according to claim 1 isconverted with excipients and carriers into a suitable administrationform.
 8. A method for the treatment and/or prophylaxis ofarteriosclerosis and hypercholesterolaemia comprising administering to asubject in need thereof an effective amount of a compound according toclaim
 1. 9. A method for the prophylaxis and/or treatment of types ofdisorders which can be treated with natural thyroid hormone comprisingadministering to a subject in need thereof an effective amount of acompound according to claim
 1. 10. The process of claim 4, wherein theintermediates of the general formula (Ia) in which X′ is —CH(OH)— areisolated prior to reduction.
 11. The method of claim 8, wherein acompound of claim 1 is administered in combination with othermedicaments.
 12. The method of claim 9, wherein a compound of claim 1 isadministered in combination with other medicaments.